Au-Kline Syndrome

A number sign (#) is used with this entry because of evidence that Au-Kline syndrome (AUKS) is caused by heterozygous mutation in the HNRNPK gene (600712) on chromosome 9q21.

Clinical Features

Au et al. (2015) reported 2 unrelated boys, aged 17 and 11 years, with a complex syndromic neurodevelopmental disorder. The patients had delayed psychomotor development with moderate intellectual disability and speech impairment. One had attention deficit-hyperactivity disorder. Both had somewhat variable dysmorphic features apparent since birth, including dolichocephaly, ridged metopic suture, long face, long palpebral fissures, ptosis, broad or sparse lateral eyebrows, underdeveloped ear helices, wide nasal ridge with dip at the nasal tip, open downturned mouth, high palate, prominent midline tongue groove, missing molars, and excess nuchal skin. Both patients had cryptorchidism and skeletal anomalies, including hip dysplasia, scoliosis, and extra lumbar vertebrae; 1 had multiple vertebral segmentation defects. One patient had planovalgus feet and crowded toes, whereas the other had postaxial polydactyly and overlapping toes. Cardiac defects included 2 small ventricular septal defects in 1 patient, and bicuspid aortic valve and aortic root dilation in the other. Additional features included hypotonia, hyporeflexia, and high pain tolerance.

Lange et al. (2016) described a boy with a complex phenotype that expanded the phenotype of AUKS. Nuchal thickening was noted at 12 weeks' gestation, but karyotype was normal. Postnatally, the child had an atrioventricular septal defect, cleft palate, renal pelvic dilatation, bilateral talipes, partial agenesis of the corpus callosum, hypotonia, and significant developmental delay. Dysmorphic features included a prominent metopic ridge, medial flare of the eyebrows, long palpebral fissures with lateral eversion of the lower eyelids, hypoplastic alae nasi, low-set prominent ears, and thick wrinkled skin in the back of the neck. He also had hypoplastic toenails, deep palmar and plantar creases, and a midline groove on his tongue. He had a shallow acetabulum and mild scoliosis. He had sagittal craniosynostosis on skull CT scan and agenesis of the corpus callosum with nodular heterotopia in the frontal horns on brain MRI. His weight and head circumference were within normal limits, but his height was above the 90th centile.

Miyake et al. (2017) described a 4-year-old Japanese boy with AUKS who had severe developmental delay, broad and laterally sparse eyebrows, long palpebral fissures, ectropion of the lateral lower eyelids, and prominent digit pads. He also had right ureteropelvic junction stenosis, left ureteral stenosis, and bilateral hydronephrosis. Brain imaging at 2 years 8 months was normal. Miyake et al. (2017) noted that previously reported patients with AUKS had ridged metopic sutures, long faces, long palpebral fissures, prominent ears, full cheeks, open mouths, high palates, genitourinary anomalies, various hand/foot abnormalities, hypotonia, high pain tolerance, and intellectual disabilities. Some patients with AUKS also had lateral sparse eyebrows, low-set ears, downturned mouths, prominent midline grooves of the tongue, cardiac anomalies, hip dysplasia, scoliosis, and thick/wrinkled skin on the neck. Multiple ear pits and creases of the earlobes were seen in their patient, and earlobe creases were described in a patient with AUKS by Au et al. (2015). Miyake et al. (2017) noted that although AUKS has many features in common with Kabuki syndrome (see 147920), the AUKS features of ridged metopic sutures, long faces, full cheeks, open mouths, prominent midline grooves of the tongue, and high pain tolerance are rarely seen in Kabuki syndrome and could be helpful in differential diagnosis.

Au et al. (2018) reported 6 new patients with AUKS and reviewed the clinical features of the previously reported 6 patients. Prenatal presentation was notable; 5 patients had increased nuchal translucency and 5 patients had hydronephrosis. Shared facial features included long palpebral fissures, shallow orbits, ptosis, broad nasal bridge, hypoplastic alae nasi, and a downturned mouth. Missing teeth were seen in 2 patients and malocclusion in at least 3. Craniosynostosis affecting the sagittal suture and/or metopic ridging was seen in one-third of patients, with involvement of the lambdoid suture in only 1 patient. A long face and mildly coarse facial features were also seen. Variable ear anomalies were present in many patients, and both sensorineural and conductive hearing loss were reported. Vision abnormalities were variable, with optic nerve abnormalities seen in at least 3 patients. Congenital heart defects were reported in 10 of 12 patients, with ventricular septal defects being the most common. Genitourinary anomalies were also common. Gastrointestinal malformations were rarely described, but motility issues (e.g., constipation) was common. All patients had global developmental delay, and older patients had moderate to severe intellectual disability. High pain tolerance was reported in at least 4 patients. Brain MRI findings were variable, with hypoplasia or agenesis of the corpus callosum being the most common. Skeletal findings, in particular vertebral anomalies, were common.

Molecular Genetics

In 2 unrelated boys with Au-Kline syndrome, Au et al. (2015) identified 2 different de novo heterozygous putative loss-of-function mutations in the HNRNPK gene (600712.0001 and 600712.0002). The mutations were found by exome sequencing. Functional studies of the variants were not performed.

Using trio-based whole-exome sequencing, Lange et al. (2016) identified a de novo heterozygous 2-bp insertion (c.931_932insTT; 600712.0003) in exon 11 of the HNRNPK gene in a boy with a phenotype consistent with AUKS. The variant was confirmed by Sanger sequencing.

By exome sequencing, Miyake et al. (2017) identified a de novo heterozygous missense mutation in the HNRNPK gene (L155P; 600712.0005) in a Japanese boy with AUKS. The variant was confirmed by Sanger sequencing and was not present in the ExAC, Exome Variant Server, or Human Genetic Variation databases or in an in-house database of 575 exomes.

Using whole-exome sequencing, Au et al. (2018) identified 5 patients with AUKS with de novo heterozygous loss-of-function variants in HNRNPK, including nonsense, frameshift, and canonical splice variants. In addition, they reported a girl (patient 10) with a de novo 264-kb microdeletion encompassing 9q21.32, which disrupts HNRNPK as well as 3 additional genes and a microRNA with no known human disease association. The common phenotype between the patients with HNRNPK truncating variants and the microdeletion supported haploinsufficiency of the HNRNPK gene as the pathogenic mechanism of AUKS.